Hexokinase 2-driven aerobic glycolysis modulates YAP1 in placental trophoblast development

Recurrent pregnancy loss (RPL) is a severe complication, and its risk is heightened by dysregulated trophoblast development. However, the underlying mechanisms remain unclear. Herein, we show that a portion of villous samples from patients with RPL display reduced hexokinase II (HK2) and Yes-associated protein 1 (YAP1) expression compared with healthy controls. Moreover, in human trophoblast stem (TS) cell models, blocking HK2 activities via exposure to 3-bromopyruvate markedly reduced cell proliferation and induced cell cycle arrest by regulating YAP1 phosphorylation and localization. This was partially reversed by the YAP signaling activator TT-10. Moreover, YAP1 contributes to aerobic glycolysis regulation by influencing HK2 activity. Together, these findings demonstrate an interplay between the Hippo/YAP1 pathway and glucose metabolism in placental trophoblast development and highlight an approach for RPL intervention.